Neuropathologic and neuroimaging evidence indicates that substantial overlap exists between Alzheimer's disease (AD) and advanced cerebrovascular (l-amyloid (AB) deposition (cerebral amyloid angiopathy, CAA). Particularly striking is the recent observation of lobar microbleeds (MB) a hallmark feature of CAA in a fifth or more of patients diagnosed with AD. CAA is a well-known cause of vessel fragility and rupture, leading to hemorrhagic strokes as well as MBs. Although more widely recognized for its role in hemorrhagic stroke, evidence of white matter ischemia with myelin loss and foci of white matter gliosis have been noted in both familial and severe sporadic CAA. Recently, associations between CAA severity and white matter damage have been identified in AD brains. The existence of a large subgroup of AD patients with advanced CAA raises the important question of how vascular amyloid impacts the cognitive profile of these subjects. This question is magnified by rapidly growing evidence that small vessel disease acts in concert with AD pathology to cause greater deficits than either process alone. Additionally, recent trial data (the finding of advanced CAA and perivascular inflammation in brains from subjects who died following experimental Aft vaccination) suggest that CAA may underlie adverse effects of anti-amyloid immunotherapies for AD. As the full meaning of AD-associated MBs is still undefined, we propose to analyze MB-positive and MB- negative AD subjects to identify the cognitive features of AD plus advanced CAA. studied both in cross- sectional and in a longitudinal analyses. We will identify the neuroimaging features of AD plus advanced CAA. studied with high-resolution MRI markers specific to both advanced CAA and AD. Although strictly lobar MBs appear to have good specificity for advanced CAA, they are at best an indirect marker, showing the effects of advanced cerebrovascular amyloid but not the amyloid itself. Thus, a second main goal of the current proposal is therefore to analyze AD patients by recently identified direct measures of CAA: 1) depletion of AIMO in cerebrospinal fluid (CSF) and 2) relative occipital burden of Pittsburgh Compound B (PiB). Preliminary data validates these markers in advanced CAA, but neither has been examined as a measure of CAA in the setting of AD. RELEVANCE (See instructions}: Successful completion of these aims will not only shed light on the natural history of this large (and heretofore unstudied) subgroup of AD patients, but also provide a vantage for future studies of their response to immunotherapy. There will be extensive use of the resources associated with the Massachusetts Alzheimer's Disease Research Center (MADRC) and its collaborators, providing key synergies with the MADRC clinical and neuropathological cores and neuroimaging resources, as well as with the long-standing CAA research program at the Massachusetts General Hospital Stroke Research Center.